Abstract
Disturbances in acid-base balance, such as acidosis and alkalosis, have potential to alter the pharmacologic and toxicologic outcomes of statin therapy. Statins are commonly prescribed for elderly patients who have multiple comorbidities such as diabetes mellitus, cardiovascular, and renal diseases. These patients are at risk of developing acid-base imbalance. In the present study, the effect of disturbances in acid-base balance on the interconversion of simvastatin and pravastatin between lactone and hydroxy acid forms have been investigated in physiological buffers, human plasma, and cell culture medium over pH ranging from 6.8–7.8. The effects of such interconversion on cellular uptake and myotoxicity of statins were assessed in vitro using C2C12 skeletal muscle cells under conditions relevant to acidosis, alkalosis, and physiological pH. Results indicate that the conversion of the lactone forms of simvastatin and pravastatin to the corresponding hydroxy acid is strongly pH dependent. At physiological and alkaline pH, substantial proportions of simvastatin lactone (SVL; ∼87% and 99%, respectively) and pravastatin lactone (PVL; ∼98% and 99%, respectively) were converted to the active hydroxy acid forms after 24 hours of incubation at 37°C. At acidic pH, conversion occurs to a lower extent, resulting in greater proportion of statin remaining in the more lipophilic lactone form. However, pH alteration did not influence the conversion of the hydroxy acid forms of simvastatin and pravastatin to the corresponding lactones. Furthermore, acidosis has been shown to hinder the metabolism of the lactone form of statins by inhibiting hepatic microsomal enzyme activities. Lipophilic SVL was found to be more cytotoxic to undifferentiated and differentiated skeletal muscle cells compared with more hydrophilic simvastatin hydroxy acid, PVL, and pravastatin hydroxy acid. Enhanced cytotoxicity of statins was observed under acidic conditions and is attributed to increased cellular uptake of the more lipophilic lactone or unionized hydroxy acid form. Consequently, our results suggest that comorbidities associated with acid-base imbalance can play a substantial role in the development and potentiation of statin-induced myotoxicity.
Highlights
Statins are cholesterol-lowering drugs commonly used to reduce morbidity and mortality associated with atherosclerotic cardiovascular diseases.[1]
To characterize the effect of pH alteration on interconversion of statins, the lactone and hydroxy acid forms of simvastatin and pravastatin were incubated with human plasma, phosphate buffer saline (PBS), and Dulbecco’s modified eagle medium (DMEM) culture medium of pH relevant to acidosis, alkalosis, and physiological pH for 24 hours
All intracellular simvastatin recovered from undifferentiated cells was in the hydroxy acid form, and no simvastatin lactone (SVL) was detected at any pH level
Summary
Statins are cholesterol-lowering drugs commonly used to reduce morbidity and mortality associated with atherosclerotic cardiovascular diseases.[1]. Statins are commonly prescribed for elderly patients who are at risk of developing acid-base imbalance as a result of multiple comorbidities such as diabetes mellitus, cardiovascular, and renal diseases. Disturbances in acid-base balance, such as acidosis and alkalosis, have potential to affect the ratio between the lactone and acid forms of statins and alter the pharmacologic and toxicologic outcomes of statin therapy. This work provides a novel translational insight into the role of disturbances in acid-base balance in development of statin-induced muscle toxicity. The effect of acidosis on statin-induced muscle toxicity is important in case of lipophilic statins, such as simvastatin. Alkaline conditions were found to have a protective effect against statin-induced myotoxicity because of inability of statin to achieve adequate intracellular concentrations as a result of conversion to the more hydrophilic ionized hydroxy acid form
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